Process of making crystalline Type II aripiprazole

ABSTRACT

Crystalline aripiprazole Type II can be formed without solid state heat treatment. Instead a liquid is used such as in crystallizing from a solvent, especially 2-propanol, dimethyl sulfoxide, or a combination thereof with ethyl acetate, or in a solvent mediated solid-solid transformation, typically in ethyl acetate.

This application claims the benefit of priority under 35 U.S.C. § 119(e)from each of (1) U.S. provisional application 60/662,552, filed Mar. 17,2005, (2) U.S. provisional application 60/692,557, filed Jun. 22, 2005,and (3) U.S. provisional application 60/739,640, filed Nov. 26, 2005,each of which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

The present invention relates to processes of making a crystalline formof7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril,also known as aripiprazole.

Aripiprazole is a compound of the formula (1).

It is a commercially marketed, pharmaceutically active substance usefulfor treatment of schizophrenia. It is disclosed in EP 367141/U.S. Pat.No. 5,006,528. The commercially marketed product is the free base of thetitle compound (1).

Solid state aripiprazole was prepared in U.S. Pat. No. 5,006,528 by atwo-fold recrystallization of crude aripiprazole from ethanol resultingin colorless flake crystals having a melting point of 139-139.5° C. Inan article of Aoki (Study on Crystal Transformation of Aripiprazole, TheFourth Japan-Korea Symposium on Separation Technology, p.937 ff (1996)),this solid state form was designated as Type I aripiprazole andidentified as an anhydrate. Aoki also teaches that the Type Iaripiprazole may be converted into a Type II aripiprazole by heating at130-140° C. for 15 hours. This product is an anhydrate as well with amelting point of 150° C. When both Type I and Type II aripiprazole wererecrystallized from an alcoholic solvent containing water up to 20%, theproduct is an aripiprazole hydrate labeled as Type III by Aoki. Type IIIaripiprazole can be converted into Type I by heating at 80° C.

WO 03/26659 (EP 1330249) teaches that the Type I aripiprazole, thealleged original solid form of aripiprazole, is significantlyhygroscopic. This document also disclosed other crystalline forms ofaripiprazole. One form (Form A) is a hydrate, the remaining (Forms B-G)are low hygroscopic anhydrates, differing with arrangement of moleculesin the crystalline lattice.

It would be desirable to form crystalline Type II of aripiprazolewithout the need for a heat treatment or heat conversion. In particular,it would be desirable to find an alternate, economically moreadvantageous process, which does not require long-term exposure to hightemperatures.

SUMMARY OF THE INVENTION

The present invention is based on the discovery of how to form the solidstate Type II aripiprazole without the use of a solid state heattreatment. Instead a liquid or solvent can be used such as bycrystallizing Type II from a solvent or by a solvent-mediatedsolid-solid transition to form Type II in a solvent slurry.

Accordingly, a first aspect of the present invention relates to aprocess, which comprises crystallizing aripiprazole Type II from asolution of aripiprazole. More particular, the process comprisescrystallizing aripiprazole dissolved in a solvent selected from thegroup consisting of 2-propanol, dimethyl sulfoxide, and mixtures thereofwith ethyl acetate.

Another aspect of the invention relates to a process for makingaripiprazole Type II, which comprises providing a solution whichcontains aripiprazole dissolved in a solvent selected from the groupconsisting of 2-propanol, dimethyl sulfoxide, and mixtures thereof withethyl acetate; crystallizing the aripiprazole from the solution to formaripiprazole crystals; and recovering the crystals to obtain isolatedcrystalline aripiprazole Type II.

A third aspect of the invention relates to a solvent-mediatedsolid-solid conversion process of making aripiprazole Type II comprisingstirring a suspension of aripiprazole Form B in a liquid medium,particularly in ethyl acetate, for a time sufficient to execute thesolid-solid transformation from Form B to Type II.

A further aspect of the invention relates to a population of crystallinearipiprazole Type II particles, wherein at least 95% of said particleshave a particle size of less than 200 microns, preferably between 50 and200 microns in some embodiments and less than 50 microns in others. Sucha population is conveniently made by one of the aforementionedprocesses, optionally with sieving.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 represents an example of the DSC curve of aripiprazole Type II.

FIG. 2 represents an example of the XRPD pattern of aripiprazole TypeII.

DETAILED DESCRIPTION OF THE INVENTION

The invention is based on a surprising finding that aripiprazole TypeII, contrary to the teachings in above-mentioned disclosures, can beformed by a process which does not require heating aripiprazole in solidstate. Instead, aripiprazole Type II may be made in a liquidenvironment. This easier route of formation is especially desirablebecause it has now been discovered that Type II aripiprazole is nothygroscopic and thus would make an excellent pharmaceutical agent fromthe commercialization, production, and handling perspectives.

As used herein “Type II” of aripiprazole means a crystallinearipiprazole substance having an x-ray powder diffraction (XRPD) patternthat substantially corresponds to that of the Type II product as definedin the above cited article of Aoki. “Substantially corresponds” is meantto cover variations/differences in the pattern that would not beunderstood by a worker skilled in the art to represent a difference incrystal structure, but rather differences in technique, samplepreparation, impurities, etc. An example of the XRPD of the Type IIaripiprazole is shown on FIG. 2.

Typically the Type II aripiprazole will also have a single meltingendotherm peak within the range of 145° C. to 150° C., especially around148-149° C., measured using differential thermal analysis (DTA) ordifferential scanning calorimetry (DSC). An example of the DSC patternof aripirazole Type II is shown in FIG. 1. The DTA and DSC values shouldbe used with a certain care as these types of data are dependant onmeasuring conditions such as heating rate, type of equipment, samplepurity, sample loading, etc.

The Type II aripiprazole is a relatively stable crystalline formsuitable for making pharmaceutical compositions on an industrial scale.The Type II aripiprazole (in pure state, i.e. free from other forms) isanhydrous, meaning it neither contains water or other solvent bound aspart of the crystal lattice. This should be distinguished from wetcrystals that have water or solvent adhered thereto. Such liquid ispermitted (e.g., a “wet” or damp crystalline substance), so long as itis not part of the regular repeating unit of the crystal lattice.Generally, the Type II aripiprazole is non-hygroscopic. However, it canbe hygroscopic if, inter alia, it is milled as discussed hereinafter.

The first process is crystallization of aripiprazole from a solvent.Such a process provides several advantages over heating aripiprazole ina solid state. The process is easily scaleable, well controllable anddoes not require thermal treatment at temperatures higher than 100° C.which minimizes the decomposition side products. Using a solvent alsoallows for purification of the product. This can be advantageous notonly for crystallization of crude aripiprazole but also for relativelypure aripiprazole. Thus, Type II can be directly precipitated withoutthe need to heat treat.

The solvents used in the present invention comprise 2-propanol, dimethylsulfoxide, and combinations thereof. The list is not exhaustive. Forexample, additional solvents and/or antisolvents can also be present inthe solution, as long as at least one of the aforementioned solvents ispresent. Generally the 2-propanol and/or dimethyl sulfoxide comprise atleast 30% by volume, more typically at least about 50% by volume, of thesolution. In one embodiment, ethyl acetate is additionally present,especially in combination with isopropanol, and typically within therange from 1 to 75% by volume, more typically 35 to 60% by volume of thetotal solvent system. Surprisingly, the additional presence of ethylacetate to the 2-propanol solvent can provide a more robustcrystallization media for precipitating Type II aripiprazole than2-propanol alone. An aripiprazole solution containing approximately a1:1 by volume mixture of isopropanol and ethyl acetate has been found tobe a useful solvent system in terms of yield and purity. In allembodiments of the present invention, the solvent(s) is/are normallyanhydrous, i.e. traces of water ordinarily present in a conventionalbatch should be controlled and, if necessary, removed. Typically thewater content within the solvent system is less than 1%.

It is surprising that the use of the above mentioned solvents incrystallization allows the formation of Type II crystals ofaripiprazole. In contrast, for example, it was discovered that alcoholssuch as methanol and ethanol produce alcoholates, that is solvates ofaripiprazole (See U.S. Provisional Application 60/628,654, filed Nov.18, 2004, the entire contents of which are incorporated herein byreference). While the bound solvent can be removed by heating, no TypeII was obtained by such desolvation. Instead, Form B aripirazole wasformed.

The crystallization of aripiprazole as Type II from the solution asdescribed above can be carried out by techniques generally known in theart. That is, a solution containing crude aripiprazole dissolved in thesolvent system of the invention is solidified by crystallizing thedissolved aripiprazole out of the solution. The aripiprazole-containingsolution can be provided in a number of ways and is not particularlylimited. For example, aripiprazole can be dissolved in the solvent or itcan be synthesized in the solvent.

In this regard, any form of aripiprazole may be used as the startingmaterial for crystallization; i.e., an isolated or un-isolated crudeproduct arisen from the synthesis of aripiprazole, which is called“crude aripiprazole” throughout this invention, or an aripiprazoleproduct already isolated such as the Types I-III or Forms A-G as made bythe techniques disclosed in the art, or an aripiprazole alcoholate suchas a methanolate or a hemiethanolate as disclosed in ProvisionalApplication 60/628,654. Typically the solvent is heated in order toincrease the solubility of the crude aripiprazole. This includes forminga suspension of aripiprazole in the solvent and then heating until thesolid dissolves or, alternatively, adding aripiprazole gradually intothe already heated or hot solvent. A “hot” solvent has a temperaturewithin the range of its boiling point to 20° C. less than its boilingpoint, typically from the boiling point to 10-15° C. below the boilingpoint of the solvent.

The concentration of aripiprazole in the solvent depends on the natureof solvent as well as the presence or absence of other dissolved orsuspended components, e.g., reactants, side-products, etc. In general,the upper limit is the maximum concentration; i.e., the saturationconcentration, at the boiling point of the solvent. Typically theconcentration is at least about 20 to 250 mg/ml.

Once the solution containing aripiprazole has been provided,crystallization can, in general, be carried out by any convenientmethod. Usually the crystallization involves cooling the solution. Thenucleation may be improved by adding a seeding crystal(s) or scratchingthe surface of the vessel. That is, the crystallization process may beinduced or aided by adding small amounts of seed crystals ofaripiprazole Type II.

The conditions of crystallization (concentration, cooling rate, etc.)may be controlled for the given solvent to result in the crystallizationof aripiprazole Type II. With regard to isopropanol, it is possible toform Type I or Type II, depending on the conditions. In general, highercrystallization temperatures favor Type II of the present inventionwhile lower temperatures favor Type I as described in U.S. ProvisionalApplication 60/628,653, filed Nov. 18, 2004, the entire contents ofwhich are incorporated herein by reference. Typically for isopropanolthe crystals should initially be formed, e.g., become separated from thesolution, at a temperature higher than 50° C. and more typically 65° C.or higher. If crystallization begins at a temperature less than 50° C.,then Type I aripiprazole is generally more favored to be formed. Incontrast to isopropanol, dimethyl sulfoxide solvent apparently does notreadily formed Type I and thus can easily crystallize aripiprazole TypeII in a more temperature independent fashion.

Other than as described above regarding the temperature concerns at thestart of crystallization, the rate of cooling is not particularlylimited and in general, it may affect the particle size of the formedcrystals. A quicker rate of cooling generally leads to smaller crystals.A spontaneous cooling rate; i.e., allowing the solution to cool withoutspecial cooling or heating measures, as well as a linear cooling rateare generally preferred, although other cooling regimes are alsocontemplated for use in the present invention. The final temperatureafter cooling may also affect the particle size, the yield and/or thepurity of the product.

As a result of crystallizing from the solvents of the invention, it isbelieved that aripiprazole Type II is easily and directly obtained. Toconfirm that the crystals are Type II, the crystals are isolated fromthe remaining solvent/solution and subjected to XRPD. The isolating ofthe crystals can be carried out by any conventional methods. In general,the solid crystalline material is recovered from the liquid portion suchas by filtration or centrifugation, optionally washed such as with thesolvent used or with the contrasolvent, and generally, though notnecessarily, dried. The drying can be conducted in vacuo, with or withapplying heat. It is an advantage of the process that the solvent may beremoved without any long-term or high-temperature drying. The dryingtemperature advantageously does not exceed 60° C. and preferably doesnot exceed 40° C. Again, it is believed that the isolated wet crystalsas well as the dried crystals are aripiprazole Type II.

Furthermore, it has been discovered that aripiprazole Type II may beprepared by a solvent-mediated solid-solid transformation of a suitablemetastable solid state form of aripiprazole in a liquid medium. Anexample of the metastable solid state form of aripiprazole is thearipiprazole Form B (as defined in WO 03/26659). The transformation mayoccur by suspending the starting material in the liquid medium (which isa liquid in which the aripiprazole is not soluble or only sparinglysoluble) and stirring the mixture for the time necessary for completingthe conversion. The degree of conversion may be monitored by suitablemethods. In general, heating or cooling the suspension is not necessary,but is not excluded. Typically the temperature is within the range of 0to 30° C. such as ambient temperature. In an example, aripiprazole FormB may be converted into aripiprazole Type II by stirring in ethylacetate suspension at room temperature for 15 hours. It is not suggestedto use water or an alcohol within the medium, as hydrates or alcoholatesof the aripiprazole might be formed, which is not suitable for thepurpose of this invention.

After completing the conversion, the produced Type II aripiprazole maybe isolated by any convenient way of separation from the medium, e.g. byfiltration or centrifugation, and optionally dried to remove the rest ofthe liquids

The processes of the present invention may be used for conversion of anundesired form of aripiprazole into the Type II aripiprazole, or for apurification of the insufficiently pure Type II aripiprazole. Inparticular, the crystallization process is well suited for this purposeas most of the impurities present in a crude starting material are wellremoved within the crystallization process of the present invention. Thepurification effect may be enhanced by using a surface active materialprior to subjecting the aripiprazole solution to the crystallization, assuch material may adsorb various impurities on its surface. Anyconventional material, for instance activated carbon, Hyflo etc., may beused for this purpose. After treatment of the aripiprazole solution withsuch material, the material is normally removed such as by filtration,before carrying out crystallization. Thus, the process of the inventionmay be used to make essentially pure Type II of aripiprazole, i.e.,essentially free from other forms of aripiprazole and/or fromstructurally related impurities. The essentially pure aripiprazole TypeII comprises more than 98% of the Type II.

If the particle size distribution obtained as a result of the process ofthe invention is insufficient for the intended purpose, e.g., thedissolution profile, bioavailability of the aripiprazole, etc., is notwithin a desired range, then sieving of the crystal particles can beused to modify the population. In general, the useful population forpharmaceutical applications should contain at least 95% of particleshaving a particle size less than 200 microns, and in some embodimentsless than 50 microns. For example, a population of aripiprazole Type IIhave a d₉₀ of 70 microns or less, more typically 50 microns or less, andfrequently within the range of 18-50 microns, can be useful in making atablet formulation. The desired population can be obtained by sievingwith one or more sieves, if necessary. Milling should be avoided aspolymorphic transitions may occur during milling. Unlike milling, thesieving process does not bring significant energy to bear on thearipiprazole crystalline material and the crystalline form is not usualadversely affected by the process.

This surprising fact relates not only to the aripiprazole Type IIprepared by the process of the present invention, but also to the TypeII prepared by methods of the prior art or any other process. Thus, aprocess of improving or adjusting particle size of aripiprazole Type II,characterized in that the aripiprazole Type II is subjected to sievingthrough a sieve of the desired mesh screen, is another aspect of thepresent invention. The desired fraction in some instances can beobtained by using two sieves with mesh sizes of a selected upper andlower limit, and fractions having particle sizes below and above thelimits are discarded or reprocessed.

Aripiprazole Type II, sieved through a sieve of the mesh size of lessthan 200 microns, preferably through sieves of mesh sizes between 50 and200 microns (=a population of particles of Aripiprazole Type II, whereinmore than 95% of particles has a particle size less than 200 microns,typically between 50 and 200 microns) and also aripiprazole Type II,sieved through a sieve of the mesh size of less than 50 microns, can beadvantageous from the standpoint of manufacturing and dissolutioncharacteristics, particularly in making pharmaceutical tablets.

The aripiprazole Type II can be formulated into a pharmaceuticalcomposition, especially a tablet or capsule, by combining the same withone or more pharmaceutically acceptable excipients. Generally the amountof aripiprazole is within the range of 1 to 50 mg per unit dose, andspecifically 2, 5, 10, 15, 20, 25, or 30 mg per tablet. Suitablecompositions are described in more detail in U.S. provisionalapplication 60/739,640, which is incorporated herein by reference.

The present invention is more particularly described and explained bythe following examples. It is to be understood, however, that thepresent invention is not limited to these examples and various changesand modifications may be made without departing from the scope of thepresent invention.

EXAMPLES Reference Example: Method to Make Type II, Aoki et al

0.3 g of aripiprazole (Type I) was placed in a glass bottle of 10 mlwith screw cap. The sample was annealed in an oven at 140° C. for 15hours. The melt was slowly. cooled to room temperature. Beige, opaqueagglomerates of needle-like and fiber-like crystals were obtained. Asmall fraction of a brown glass was also present. The yield was notdetermined.

-   DSC: Irregular endothermic effects between 90-120° C. Melting peak    around 147-150° C.-   TGA: Only gradual mass loss above 220° C. (thermal degradation).-   XRPD: Similar to the XRPD spectrum of Type II reported by Aoki et    al.-   HSM: Agglomerates of plate and fiber-like crystals, mainly    opalescent to nearly opaque. Between 100-125° C. there is a clear    solid-solid transition (crystal jumping and cracking). All crystals    melt between 145-155° C.

Example 1

500 mg of aripiprazole (Type I) was suspended in 10 ml of ethyl acetateat room temperature. The suspension was stirred in a closed bottle withscrew cap for about 24 hours. The crystals were isolated by filtrationover a P3-glass filter (reduced pressure) and air-dried overnight atambient conditions. A white, fine powder with some lumps was obtained.The yield was 410 mg.

DSC: faint (evaporation) endotherm between 50-90° C., an asymmetricendotherm between 115-135° C. and a melting peak around 148-149 C.

TGA: minimal mass loss below 80° C. (some water or residual solvent).Gradual mass loss above 220° C. (thermal degradation).

XRPD: Corresponds to Type II.

HSM: Small and irregular plates and fragments of plates.

Example 2

10 g of aripiprazole (Type I) was suspended in 50 ml of 2-propanol. Themixture was refluxed. To the hot suspension, 80 ml of 2-propanol wasadded. A clear solution was obtained. Reflux was continued for 10minutes. The heating bath was removed, crystallization started after 4minutes. (T=73° C.). The suspension was allowed to cool to roomtemperature and stirring was continued for 16 hours. The solid wasisolated by filtration over a P3 glass filter and dried in a vacuum ovenat 40 C for 2 hours. A white, crystalline powder with a yield of 9.42 gwas obtained.

The crystals were dried at 90° C. and under vacuum for an additional 16hours and analyzed.

DSC: An (asymmetric) endotherm between 95-135° C. and a melting peakaround 148-149° C.

TGA: No mass loss up to 220° C. detected.

XRPD: Corresponds to Type II.

KF: no water detected

HSM: Mainly isolated plates. The particle size of the crystals isbetween 10-60 μm.

Example 3

1.01 g of aripiprazole (form B) was dissolved in 5 ml of DMSO at reflux.The hot solution was allowed to cool to room temperature. After 15minutes, the flask was scratched with a spatula in order to inducenucleation sites. After an additional 30 minutes crystallization couldbe observed. Crystallization occurred in the next 45 minutes. Then, thecrystals were isolated by filtration over a P3-glass filter (reducedpressure) and dried over the weekend at 40° C. and under vacuum. Shinyand colorless to slightly bluish or greyish crystals were obtained. Theyield was 180 mg.

DSC: Irregular endotherm between 95-120° C. and a large melting peakaround 148-150° C.

XRPD: Corresponds to Type II.

HSM: Thick needles and plates with different crystal dimensions.

Example 4

40.0 g of aripiprazole (Type I) was suspended in 520 ml of 2-propanol.The mixture was stirred and heated to reflux, resulting in a clearsolution. Reflux was continued for about 45 minutes. The heating bathwas removed and about 80-100 mg of aripiprazole, Type II, was added asseed in 4 steps. During addition of the seed, the solution was stirred.After the fourth addition, crystallization started. The innertemperature was about 68° C. The suspension was allowed to cool to roomtemperature (R.T.). After cooling, an additional 20-40 mg ofaripiprazole, Type II, was added. The suspension was overnight stirredat R.T. The solid was isolated by filtration over a P3 glass filter anddried overnight in a vacuum oven at 40 C. An off-white, crystallinepowder with a greyish or bluish tinge was obtained. The yield was 38.48g.

DSC: Corresponds to Type II.

TGA: No mass loss up to 220° C. detected.

XRPD: Corresponds to Type II.

HSM: Prism-like plates and rods, typically between 20-200 μm. Fewparticles >200 μm.

Example 5

100 g Aripiprazole was suspended in 1.3 l of 2-propanol. The mixture wasrefluxed. After 1 hour a clear solution was obtained. The suspension wasallowed to cool to room temperature, wherein at ±73° C. the solution wasseeded with ±50 mg of aripiprazole Type II crystals. Crystallizationstarted at that temperature. Stirring was continued for 16 hours. Thesolid was isolated by filtration over a P3 glass filter. The solid wasdried in a vacuum oven at 40° C. for 24 hours. Yield: 94 g of Type IIaripiprazole

Example 6

140 g of aripiprazole was suspended in a mixture of 1 liter 2-propanoland 1 liter ethyl acetate. The stirred suspension was heated to reflux.A clear solution was obtained. Reflux was maintained for about 15minutes. The stirred solution was allowed to cool to 55° C. At 55° C.the solution was seeded with 1 g of aripiprazole Type II crystals andprecipitation commenced. The seeded solution was cooled to 4° C. inabout 1 hour and 20 minutes. The resulting suspension was stirred at 0°-4° C. for 30 minutes. The solid was isolated by filtration and dried ina vacuum oven at 40° C., <10 mbar for 16 hours. The yield was 125 g(89%) of Type II aripiprazole.

Each of the patents, patent applications, and journal articles mentionedabove are incorporated herein by reference. The invention having beendescribed it will be obvious that the same may be varied in many waysand all such modifications are contemplated as being within the scope ofthe invention as defined by the following claims.

1. A process, which comprises: crystallizing aripiprazole Type II from asolution of aripiprazole dissolved in a solvent selected from2-propanol, dimethyl sulfoxide, or mixtures thereof and optionallyfurther comprising ethyl acetate.
 2. The process according to claim 1,wherein the solvent has a water content of less than 1%.
 3. The processaccording to claim 1, wherein said solvent is 2-propanol.
 4. The processaccording to claim 1, wherein said solvent is a mixture of 2-propanoland ethyl acetate.
 5. The process according to claim 4, wherein2-propanol and ethyl acetate are present in an amount of about 1:1 byvolume.
 6. The process according to claim 1, which further comprisesisolating said crystalline aripiprazole Type II from said solvent. 7.The process according to claim 6, wherein said isolating comprisesfiltering and/or drying.
 8. A process for making aripiprazole Type II,which comprises: providing a solution which contains aripiprazoledissolved in a solvent selected from 2-propanol, dimethyl sulfoxide, ormixtures thereof and optionally further comprising ethyl acetate;crystallizing said aripiprazole from said solution to form aripiprazolecrystals; and recovering the crystals from the solvent to obtainisolated crystalline aripiprazole Type II.
 9. The process according toclaim 8, wherein said providing step comprises forming said solution aspart of a synthesizing route to make aripiprazole.
 10. The processaccording to claim 8, wherein said providing step comprises dissolvingaripiprazole in said solvent to form said solution.
 11. The processaccording to claim 8, wherein said solvent is 2-propanol.
 12. Theprocess according to claim 8, wherein said solvent is a mixture of2-propanol and ethyl acetate in an amount of about 1:1 by volume. 13.The process according to claim 8, wherein said crystallizing comprisescooling said solution.
 14. The process according to claim 8, whereinsaid crystallizing comprises adding a seeding crystal of aripiprazoleType II.
 15. The process according to claim 8, wherein said recoveringstep comprises separating said crystals from said solvent by filtrationand drying said separated crystals.
 16. The process according to claim15, wherein said drying is carried out at a temperature of 40° C. orless.
 17. The process according to claim 8, which further comprisessieving said crystalline aripiprazole Type II to obtain a desiredparticle size distribution.
 18. A solvent-mediated solid-solidconversion process for making aripiprazole Type II, which comprisesstirring a suspension of aripiprazole Form B in ethyl acetate for asufficient time to obtain conversion to aripiprazole Type II.
 19. Theprocess according to claim 18, wherein said stirring is carried out at atemperature within the range of 0 to 30° C.
 20. The process according toclaim 19, which further comprises sieving said crystalline aripiprazoleType II to obtain a desired particle size distribution.
 21. The processaccording to claim 13, wherein said solvent comprises at least about 50%by volume of 2-propanol; and wherein said crystallization begins at atemperature of 65° C. or higher.